Hypomethylation‐mediated activation of cancer/testis antigen KK‐LC‐1 facilitates hepatocellular carcinoma progression through activating the Notch1/Hes1 signalling

Abstract

Objectives: Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen reactivated in several human malignancies. So far, the major focus of studies on KK-LC-1 has been on its potential as diagnostic biomarker and immunotherapy target.However, its biological functions and molecular mechanisms in cancer progression remain unknown. Materials and Methods: Expression of KK-LC-1 in HCC was analysed using RT-qPCR,Western blot and immunohistochemistry. The roles of KK-LC-1 on HCC progression were examined by loss-of-function and gain-of-function approaches. Pathway inhibitor DAPT was employed to confirm the regulatory effect of KK-LC-1 on the downstream Notch signalling. The interaction of KK-LC-1 with presenilin-1 was determined by co-immunoprecipitation. The association of CpG island methylation status with KK-LC-1 reactivation was evaluated by methylation-specific PCR, bisulphite sequencing PCR and 5-Aza-dC treatment. Results:We identified that HCC tissues exhibited increased levels of KK-LC-1. High KK-LC-1 level independently predicted poor survival outcome. KK-LC-1 promoted cell growth, migration, invasion and epithelial-mesenchymal transition in vitro and in vivo.KK-LC-1 modulated the Notch1/Hes1 pathway to exacerbate HCC progression through physically interacting with presenilin-1. Upregulation of KK-LC-1 in HCC was attributed to hypomethylated CpG islands.

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“…The DLL4-mediated Notch pathway plays a vital role in regulating angiogenesis, especially in regulating embryonic vascular development and tumor angiogenesis[95,96]. The DLL4/Notch pathway in adult vasculature mainly inhibits the activity, migration, and differentiation of endothelial cells, thereby impeding angiogenesis and maintaining vascular stability[97,98]. Generally, vascular endothelial growth factor (VEGF) induces DLL4 production in endothelial cells, which promotes the activation of the Notch signaling pathway, downregulates VEGF3, and promotes endothelial cell sprouting[99].…”

CAR T-Cell Cancer Therapy Targeting Surface Cancer/Testis Antigens

“…Further investigations must be performed to elucidate the potential of targeting SP17 by immunotherapy. CT83 is also expressed in multiple cancers, such as breast, gastric, and lung cancers, and the expression can be upregulated by DNMTis ( 62 – 67 ). CT83 as a target for TCR-based therapies has shown promising results ( 64 , 68 ), but the potential of the antigen as a target for CAR T-cell therapy remains unexplored.…”

MicroRNA-3163 targets ADAM-17 and enhances the sensitivity of hepatocellular carcinoma cells to molecular targeted agents

“…This results in the release of the Notch intracellular domain (NICD) for translocation into the nucleus to mediate the transcription of pro-survival or anti-apoptosis genes, such as Survivin, B-cell lymphoma-2, or inhibitors of apoptosis proteins (IAPs) [26][27][28] . Increasing evidence demonstrated that inhibition of the activation of the Notch pathway may enhance the efficiency of antitumor agents in HCC cells 29,30 . Therefore, targeting ADAM-17 may be a novel strategy for inhibiting Notch activation and enhancing the sensitivity of HCC cells to antitumor treatment.…”